RESUMO
Misfolding and fibrillar aggregation of Aß is a characteristic hallmark of Alzheimer's disease and primarily participates in neurodegenerative pathologies. There has been no breakthrough made in the therapeutic regime of Alzheimer's disease while the pharmacological interventions against Aß are designed to sequester and clear Aß burden from the neurological tissues. Based on the physiological relevance of Aß, therapeutic approaches are required to inhibit and stabilize Aß fibrillization, instead of cleaning it from the neurological system. In this context, we have designed a selenadiazole-based library of compounds against the fibrillization paradigm of Aß. Compounds that completely inhibited the Aß fibrillization appeared to stabilize Aß at the monomeric stage as indicated by ThT assay, CD spectrophotometry, and TEM imaging. Partial inhibitors elongated the nucleation phase and allowed limited fibrillization of Aß into smaller fragments with slightly higher ß-sheets contents, while noninhibitors did not interfere in Aß aggregation and resulted in mature fibrils with fibrillization kinetics similar to Aß control. Molecular docking revealed the different binding positions of the compounds for three classes. Complete inhibitors alleviated Aß toxicity to SH-SY5Y neuroblastoma cells and permeated across the blood-brain barrier in zebrafish larvae. The amino acid residues from Aß peptide that interacted with the compounds from all three classes were overlapping and majorly lying in the amyloidogenic regions. However, compounds that stabilize Aß monomers displayed higher association constants (Ka) and lower dissociation constants (Kd) in comparison to partial and noninhibitors, as corroborated by ITC. These results support further structure activity-based preclinical development of these selenadiazole compounds for potential anti-Alzheimer's therapy.